Using RNA interference to inhibit the synthesis of PCSK9 in the liver may be a new approach to lowering LDL cholesterol levels, a phase I study in healthy volunteers with elevated cholesterol suggested.

A single infusion of the intravenous RNA interference drug ALN-PCS resulted in a rapid drop in circulating PCSK9 levels accompanied by significant reductions in LDL cholesterol, according to Kevin Fitzgerald, PhD, of Alnylam Pharmaceuticals, which is developing the drug, and colleagues.

At the highest dose evaluated, there was an average LDL cholesterol reduction of 40% from baseline relative to placebo (P<0.0001), they reported online in The Lancet.

The drug was well-tolerated, with a similar rate of treatment-emergent adverse effects with ALN-PCS and placebo (79% versus 88%).

"These results support the further assessment of ALN-PCS in patients with hypercholesterolemia, including those being treated with statins," Fitzgerald and colleagues wrote. "This study is the first definitive clinical proof of concept in human beings of an RNA interference drug being used to lower a liver-derived protein (PCSK9), thereby resulting in favorable changes in a clinically validated endpoint (LDL cholesterol)."

Previous studies have shown that monoclonal antibodies designed to block PCSK9 outside of the hepatocyte effectively reduce LDL cholesterol levels. ALN-PCS, which is delivered using a lipid nanoparticle, differs in that it inhibits synthesis of PCSK9 inside the hepatocyte and affects both intracellular and extracellular functions of the protein.

Based on promising preclinical results, the researchers evaluated ALN-PCS in 32 healthy volunteers (94% male) with serum LDL cholesterol levels of 3.00 mmol/L (116 mg/dL) or higher. They were randomized 3:1 to a single 1-hour infusion of ALN-PCS (one of six different doses ranging from 0.015 to 0.400 mg/kg) or placebo. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions.

Average LDL cholesterol levels at baseline were 3.7 mmol/L (143 mg/dL) in the drug group and 3.9 mmol/L (151 mg/dL) in the placebo group.

The ALN-PCS infusion was well-tolerated and there were no serious adverse events related to the drug. One participant who received a lower dose (0.045 mg/kg) was diagnosed with bilateral pulmonary emboli and deep vein thrombosis on day three, but that was determined to be unrelated to the drug based on the participant's medical history.

The most common treatment-emergent adverse event was rash, which occurred in half of patients in both the drug groups and the placebo group, and was probably related to the other medications given before the infusion, according to the researchers.

There were no dose-dependent changes in laboratory values or concentrations of inflammatory markers.

In an accompanying editorial, John Burnett, MD, PhD, and Amanda Hooper, PhD, of the University of Western Australia, noted some limitations of the study, including the small sample size, the inclusion of few women, and the need for intravenous infusion.

"Larger multidose studies of extended duration without the use of pre-medication are needed to confirm the safety and efficacy of ALN­-PCS and should be helpful in determining the optimum dose and regimen to maximize reduction in LDL cholesterol," they wrote.

Christie Ballantyne, MD, of Baylor College of Medicine in Houston, noted similar limitations in an email but said that "this is an exciting demonstration that new technologies such as small interfering RNA can be used for novel targets to potentially impact cardiovascular disease."

He cautioned, however, that "the possible intracellular functions are not known, and we do not know for sure if this small interfering RNA is completely specific (i.e., are there any off-target effects or immunological reactions)."

Other issues to be considered are the fact that the reductions in LDL cholesterol seen with ALN-PCS were not as great as those seen with the monoclonal antibodies blocking PCSK9, as well as the administration method, according to Ballantyne.

"The IV approach used in this study was for proof of concept and almost certainly will not be used in clinical practice to treat a chronic condition," he wrote.

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